Innovating towards an HIV vaccine

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HIV: A Tricky Virus

Making an HIV vaccine is a difficult and complex task that
has eluded scientists for more than 35 years.

Conventional vaccines such as live attenuated and killed virus fail against the highly
variable and evasive HIV. Our approach is based on the induction of broadly neutralizing
antibodies (bnAbs) to the envelope trimer (green) on the surface of the virus.

HIV Envelope Trimer (Env)

Env houses the machinery that allows HIV to infect cells; it is the sole target of
bnAbs.

At
the heart of difficulty in eliciting bnAbs is the nature of Env, which is a compact protein
structure highly decorated with sugars (purple) and difficult for Abs to recognize. We have
determined the molecular structure Env and have defined the sites on Env recognized by bnAbs
in molecular detail. These studies have facilitated the precise design of our vaccine
candidates.

bnAbs and Our Approach

What are bnAbs?

They are antibodies able to neutralize
(inactivate) a large proportion of global circulating HIV strains. They arise in
some HIV-infected individuals usually after several years of infection. Through
encounter with many different viruses (immunogens) antibodies evolve to
recognize a variety of shapes exhibited by distinct viral strains.

The bnAb challenge

The challenge, and essence of the bnAb approach
to HIV vaccine design, is then to generate bnAbs in HIV-uninfected humans. We do
not have the luxury of presenting many different immunogens over several years.
In vaccination, we must present a manageable number of immunogens over a limited
time period.

CHAVI-ID Iterative Rational Approach to HIV Vaccine
Design

We
propose a rational vaccine design strategy in which a small number of well-designed
immunogens are used in sequence. Immunogens are designed based on molecular level
understanding of the interaction of bnAbs with the virus and on the biology of Ab
responses.

Equally important is the optimization of immunization
strategies. We vigorously pursue novel immunogens and immunization strategies in
pre-clinical models with the aim of bringing them into the clinic as soon as possible to
yield an HIV vaccine.

Our Philosophy

We enter the clinic only with immunogens for which we
have convincing evidence in preclinical animal models that they behave according to
design.

Additionally, we emphasize that each immunogen that
enters clinical studies should test key hypotheses in our overall strategy.

Natural infection: lineage-based design

Reductionist design

Our Accomplishments

Immunogens (grey) entering the clinic (eOD-GT8 and BG505 SOSIP) and initiating GMP manufacturing (N332-GT5 and MT145K) in 2018 and their targets (black) on HIV Env.

Our first three immunogens (top) are currently
entering manufacturing or Phase I clinical trials, each targeted to a different bnAb
site on Env.

Who We Are

The CHAVI-ID has 19 Principal Investigators working on different aspects of designing
and evaluating an HIV vaccine across the US and the World. The CHAVI-ID is led by Dr
Dennis Burton at The Scripps Research Institute in La Jola, California.

Joint Publications and Partnerships

We have worked together extremely well as a team, as evidenced by our 142
high-profile joint manuscripts, but also by our successful collaborations. Those
collaborations and partnerships facilitate the staged process during which we
proceed from Ab and Env discoveries through immunogen design to animal testing and
ultimately to the clinic.

Vaccine Product Concept Pipeline

We have a rich pipeline of highly innovative vaccine concepts that progress through
early laboratory design, preclinical testing, iterative design, GMP manufacturing,
and eventually human Phase I trials. We continuously prioritize and re-evaluate our
candidates, discarding designs that fail at critical junctures, and advancing only
the best-in-class vaccine product candidate with convincing preclinical
evidence.